Restless Legs Syndrome (RLS) is a common, dopamine- responsive, sensory-motor disorder whose symptoms predominant at night and often lead to significant sleep loss and changes in one's quality of life. Altered CNS iron metabolism may play a pivotal role in RLS. Decreasing serum ferritin has been shown to correlate with increasing RLS symptoms. RLS patients have been found to have decreased CSF ferritin and increased CSF transferrin, which suggests a decrease in brain iron stores. Finally, open-labeled, non-controlled iron therapy has been effective in treating some patients with RLS. We have developed preliminary data strongly supporting our basic model that RLS results from altered dopaminergic mechanisms, which are precipitated by a relative or absolute reduction of iron in the brain. We have also developed data that indicate there may be a decrease in the normal transfer of iron from serum to brain tissue possibly related to abnormal transport across the blood brain barrier. This indicates that the use of IV iron might at least partly correct the brain iron deficits in RLS. We will, therefore, test the hypothesis that: (1) IV iron therapy will improve the CNS iron status. (2) IV iron therapy will improve symptoms in RLS patients. (3) Improvements in CNS iron status with IV iron treatment will parallel improvements measures of RLS. And, (4) the response to IV iron therapy differs based upon age at onset of RLS symptoms. A 1000 mg of iron or placebo will be given as a single intravenous dose to RLS patients in a randomized, double-blind trial. It is anticipated that a single IV treatment will provide relief of RLS symptoms for an extended period of time (2-12 months). Post-infusion changes in CNS iron status will be evaluated using CSF measurements of ferritin and other iron- related proteins and MRI measurements of brain iron stores. Post-infusion changes in RLS will be assessed using standard subjective (Diary; rating scale) and objective (PSG, SIT, Leg Activity Meters) measures of clinical status. CSF and serum iron values, MRI measures of brain iron and full clinical evaluations with sleep and immobilization tests will be obtained prior to treatment, two weeks after treatment and again at 12 months later or when symptoms return. Clinical ratings, Leg Activity Meter recordings and serum ferritin will be obtained monthly after treatment. CSF ferritin changes will be compared to those predicted from our prior studies. Symptoms will be correlated with CSF ferritin and MRI iron values. Our studies demonstrated possible differences in response to iron for early-and late-onset RLS. So treatment response based on the age of symptom onset will be evaluated separately. An expected finding that IV iron reduces the brain iron insufficiency and dramatically reduces the RLS symptoms strongly supports our model of RLS caused by brain iron insufficiency.